A comprehensive evaluation of nucleoside transport by tumor and by normal proliferative cells is in progress. L1210 murine lymphocytic leukemia cells maintained as ascites in BD2F1 mice are used as the primary tumor model. Mature adsorptive and immature proliferative epithelial cells isolated from the villi and the crypts of the small intestine are used to study nucleoside transport by normal drug-sensitive cells. Multi-faceted investigations with metabolically competent cells, metabolically altered (ATP depleted) cells, and membrane vesicles, as well as studies with nonmetabolizable analogs as "model" substrates, are being used to determine the kinetic and physiological properties for the transport of natural nucleosides by tumor and by normal cells. The role of metabolism, especially phosphorylation, in the transport process is being considered. Competition studies between unlabeled nucleoside analogs and labeled natural nucleosides for transport by the same carrier are used to elucidate the structural specificity of the transport mechanism(s) in each cell type. These investigations will help us to understand whether or not the carrier-mediated uptake of nucleoside analogs contributes to the therapeutic response and selective action, or if it can be exploited to such ends by further structural modifications of the analogs.